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Inflammatory Cytokine as Attractive Target for Cancer Treatment: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Hyang-Mi Lee
,
Hye-Jin Lee
, Ji-Eun Chang

The inflammatory tumor microenvironment consists of inflammatory cells, chemokines, cytokines, and signaling pathways. Among them, inflammatory cytokines play an especially pivotal role in cancer development, prognosis, and treatment. Interleukins, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), interferons, and vascular endothelial growth factor (VEGF) are the representative inflammatory cytokines in various cancers, which may promote or inhibit cancer progression. The pro-inflammatory cytokines are associated with advanced cancer stages, resistance to immunotherapy, and poor prognoses, such as in objective response and disease control rates, and progression-free and overall survival.

  • inflammatory tumor microenvironment
  • inflammatory cytokine
  • cancer development

1. Colorectal Cancer

Colorectal cancer (CRC) refers to a malignant tumor composed of cancer cells in the large intestine. CRC is largely divided into colon or rectal cancer, depending on where cancer occurs. The incidence risk of CRC is associated with risk factors such as physical inactivity, age, race, or sex [1]. Chronic inflammation is considered to have a strong association with the early stages of tumor onset. CRC commonly occurs via a somatic mutation in a gene that encodes a part of the Wnt signaling pathway; hereditary mutations, such as nonpolyposis colorectal cancer (Lynch syndrome) [2]; or familial adenomatous polyposis [3]. Inherited cases can be prevented or delayed by anti-inflammatory treatment [4][5]. Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, increase the risk of CRC related to colitis with poor prognoses [6][7]. Dietary and gut microbiota also affect the progression of chronic enteritis [8][9][10][11][12][13]. Gut microbial distribution changes as CRC progresses, and this change is related to pathological tumor characteristics [14][15]. While certain types of intestinal bacteria may protect the host by promoting an anti-inflammatory immune system, others can induce inflammation or mutation [8][9][10][11][12][13]. Since CRC is closely associated with chronic inflammation, various studies for inflammatory cytokines in CRC have been evaluated.
Tumor necrosis factor-alpha (TNF-α) is a well-known tumor-suppressive cytokine that induces apoptosis in specific types of cells. On the other hand, it promotes tumors so that inflammation can proceed to cancer [16][17][18]. Colitis and colitis-associated colon cancer (CAC) proceeded fast in a TNF-α–IL-10 (interleukin (IL)-10)-deficient mouse model compared with an IL-10-deficient mouse model. In this study, TNF-α acted as a protective factor against inflammation and a tumor suppressor [19]. When TNF-α plays a tumor promoter role, a TNF-α inhibitor can be an attractive targeted treatment. In a study by Liu et al., a combination therapy of 5-fluorouracil (5-FU) and infliximab (TNF-α inhibitor) showed better outcomes than 5-FU monotherapy [20]. In more than 30% of CRC cases, granulocyte–macrophage colony-stimulating factor (GM-CSF) expression is high. GM-CSF is produced in the hematological part, which may increase anti-cancer immune responses. Overexpression of GM-CSF was strongly associated with increased overall survival rates of CRC patients [21]. Interestingly, when anti-programmed death-1 (PD-1) was used to treat a GM-CSF-silenced mice model, 25% tumor remission was found, while 50% tumor remission was observed from a GM-CSF-secreting mice model [21]. The combination of anti-PD-1 and GM-CSF showed synergetic anti-cancer effects. Another overexpressed inflammatory cytokine in CRC is IL-6. Inhibition of IL-6 or its receptors in a CAC-induced mouse model revealed a decreased tumor burden [22][23]. IL-1β also plays an important role in CRC oncogenesis with increased Toll-IL-1 receptor signaling [24][25]. Furthermore, the IL-1 receptor antagonist inhibited the metastatic process of CRC by suppressing the IL-1α/PI3K/NF-κB (nuclear factor-κB) pathway [26]. A meta-analysis of serum IL-6 in CRC patients was performed, with a total of 17 studies. IL-6 is mainly produced by T cells, macrophages, and endothelial cells. Elevated serum IL-6 levels correlated with worse overall and disease-free survival rates for CRC [27]. Other inflammatory cytokines such as IL-8, IL-1 receptor antagonist (IL-1RA), and IL-6 were proven to be associated with advanced CRC [28]. The inflammatory cytokines were confirmed to be attractive biomarkers for CRC diagnosis and/or prognosis. Several clinical trials targeting inflammatory cytokines in CRC have been initiated. A phase I/II trial using antibody targeting IL-6 (siltuximab) [29], and a phase III trial of recombinant TNF receptor (etanercept) [30], failed to induce a clinical response. However, in metastatic CRC, MABp1 (IL-1α-targeted antibody) proved to be safe and effective in a phase I study [31]. The IL-1β inhibitor is known to increase the anti-tumor efficacy of 5-FU. In a phase II clinical trial using 5-FU, bevacizumab, and anakinra (IL-1β and α inhibitor) for patients with metastatic CRC, promising activity and a controllable safety profile were shown [32].

2. Pancreatic Cancer

Pancreatic cancer is one of the most disastrous cancers and shows a very poor prognosis. Current standards of care for pancreatic cancer are surgical resection with chemotherapy [33]. It shows the lowest 5-year survival rate among cancers between 2007 and 2013 [34]. In most pancreatic cancer cases, it is symptomless until it progresses, and this leads to a poor survival rate. Pancreatic cancer has some relevant risk factors, including cigarette smoking, diabetes mellitus, chronic pancreatitis, and obesity [35][36][37][38][39]. Recently, inflammation has been getting attention because it affects the development and progression of pancreatic cancer. The inflammation process is associated with some carcinogenic processes [40]. Several inflammatory cytokines are known to be related to the oncogenesis of pancreatic cancer.
IL-6 is a pro-inflammatory cytokine that shows diverse functions of cell multiplication, injury, infection, and inflammation [41]. It affects tumor cells to develop pancreatic cancer by controlling vascular endothelial growth factor (VEGF) secretion [42]. Targeting IL-6 was suggested to be one of the therapeutic approaches for pancreatic cancer [43]. IL-8 plays a key role in promoting the angiogenesis of pancreatic cancer. Primary sources for IL-8 are macrophages, platelets, and epithelial cells. IL-8 showed high levels in the serum of pancreatic cancer patients and in the human pancreatic cancer cell line [44][45]. The elevated IL-8 level was related to the low survival rate of pancreatic cancer patients, which has led it to be considered as a marker for prognosis [46]. Interestingly, serum levels of IL-6, IL-8, IL-10, and IL-1RA were significantly increased in pancreatic cancer patients. These cytokine levels were associated with worse survival rates, poor performance status, and/or weight loss [47]. TNF-α is associated with acute and chronic inflammation, autoimmune disease, and inflammation related to cancers [48]. It has two receptors: (i) TNF-receptor 1, which is distributed in all types of cells with a death domain that leads to apoptosis; (ii) TNF-receptor 2, which is only distributed in hematopoietic cells without a death domain. According to the study with a pancreatic-cancer-induced mouse model, TNF-α accelerated tumor growth and metastasis. Furthermore, anti-TNF-α treatment significantly inhibited tumor progression [49]. IL-1β is known to be related to inflammation responses [50], cancer progression [51], and cancer cell invasiveness [52] in pancreatic cancer. In this manner, IL-1β has attracted attention as another therapeutic target for pancreatic cancer. Macrophage migration inhibitory factor (MIF) appears to have a function as a pro-inflammatory cytokine that controls immune and inflammatory responses [53]. MIF is also known to be associated with tumor survival and progression [54][55]. From the phase I clinical study of imalumab (a fully human recombinant antioxidized MIF antibody), the maximum tolerated and biologically active doses have been investigated in pancreatic cancer patients [56]. Transforming growth factor-beta (TGF-β) directly inhibits cell proliferation in pancreatic cancer and controls immune response [57]. In a phase I/II study, a TGF-β2-specific inhibitor was used as second-line therapy, and it showed significant improvements in clinical response compared with the current standard of care [58].

3. Breast Cancer

Breast cancer is a disease that makes the cells in the breast grow out of control. Breast cancer shows the highest incidence and cause of death in women [48]. It results in 14% of total cancer deaths worldwide [59]. Risk factors for breast cancer include age; genetic mutations, such as BRCA1 and BRCA2; reproductive history, and obesity. The initiation process of breast cancer is not clear; however, inflammation has been suggested as a cause for tumor initiation, progression, angiogenesis, and metastasis [60]. Inflammation is closely related the cancer, in that cell proliferation is mainly derived from inflammatory molecules.
TNF-α promotes the activation, differentiation, survival, or death of cancer cells under specific conditions. It also controls immune and inflammatory responses [61]. TNF-α is rarely detected in healthy women’s serum, while it exists in high levels in breast cancer patients [62][63]. The main cell sources for TNF-α are T cells and macrophages. When 93 breast carcinoma samples were analyzed, 97% of samples were positive for TNF-α. Among them, 61% were considered to be high-grade TNF-α. There was no correlation between TNF-α positivity and relapse-free or overall survival [64]. Anti-TNF-α treatment using a monoclonal antibody (infliximab) against a TNF receptor appears to repress tumor growth, induce tumor degeneration, and inhibit bone metastases in breast cancer-induced mice [65]. TGF-β1 is considered as a prognosis marker for breast cancer. It is mainly produced by T cells and macrophages. Breast cancer patients with high TGF-β1 plasma levels had significantly worse overall and disease-free survival rates [66]. Elevated TGF-β1 levels in metastatic axillary lymph node tissue were associated with metastatic axillary lymph node numbers and tumor size [67]. In breast cancer mouse models, blocking TGF-β signaling was effective in decreasing tumor growth and metastasis [68]. IL-6 was suggested to be another prognostic biomarker of breast cancer. In a study with 87 patients who had hormone-refractory metastatic breast cancer, high levels of IL-6 were notably related to poor survival [69]. IL-12 controls the immunity and inflammatory reactions that mediate cancer progression. It has pro-inflammatory functions via activating cytotoxic immune cells [70]. A phase II clinical study (NCT04095689) using chemotherapy and pembrolizumab plus IL-12 gene therapy with triple-negative breast cancer is ongoing. The combination of chemotherapy and pembrolizumab was proven to enhance the anti-tumor efficacy. In addition, IL-12 gene therapy stimulates the anti-tumor immune response [71]. Gene therapy based on GM-CSF has been proven for its efficacy and safety through clinical trials. In the phase I study, various cancers, including breast cancer, were treated with oncolytic herpes simplex virus expressing GM-CSF. The anti-tumor immune response and tumor necrosis were observed as having a safe profile [72].

4. Gastric Cancer

The incidence and mortality rates of gastric cancer have been constantly declining. However, it is still the fifth most common cancer and the fourth leading cause of deaths related to cancer [59]. Among the many factors influencing gastric cancer, chronic atrophic gastritis is most closely related to the occurrence of gastric cancer [73]. Gastric inflammation is commonly caused by Helicobacter pylori and autoimmune gastritis. Gastric inflammation leads to atrophic gastritis, metaplasia, dysplasia, and adenocarcinoma [74][75]. In addition, chronic gastric inflammation increases the risk of gastric cancer. Various cytokines secreted from immune and epithelial cells in chronic inflammation are identified, and they are expected to be potential targets for gastric cancer treatment.
In a clinical study with gastric ulcer patients, IL-17 was proved to be important in the inflammatory response to Helicobacter pylori. Moreover, IL-17 also affects the Helicobacter pylori-associated diseases. Including interferon (IFN)-γ showed increased levels in gastric mucosa after Helicobacter pylori infection. IFN-γ upregulates NF- κB signaling so that carcinogenesis occurs [76]. Accordingly, inhibition of IFN-γ can be a key treatment for gastric cancer. IL-6 is a pro-inflammatory cytokine that promotes the growth and progression of gastric cancer. It was identified that IL-6 is overexpressed in the stromal portion of gastric cancer and the elevated IL-6 stimulates the Jak1-STAT3 pathway in gastric cancer via paracrine signaling. This leads to the development of stroma-induced chemoresistance. To overcome the resistance to chemotherapy by targeting IL-6, tocilizumab (anti-IL-6 receptor monoclonal antibody) was used in treatment and it effectively enhanced the anti-tumor effect of chemotherapy in gastric cancer [77]. Several inflammatory cytokines were evaluated to determine whether they may be applied as prognostic biomarkers. Gastric cancer patients with high-IL-17-serum concentrations showed significantly lower 5-year survival rates compared with patients with low IL-17 rates [78]. The expression of IL-22 receptors in gastric cancer appears to be associated with lymphatic invasion and poor prognosis [79]. Furthermore, high levels of IL-6 were also related to poor prognosis with recurrence and the overall survival rates of gastric cancer patients [80]. In a clinical trial, gene therapy using GM-CSF has been proven useful for its efficacy and safety against gastric cancer [72]. Currently, PD-1/programmed death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) are often selected for cancer treatment. ICIs inhibit the immunosuppressive mechanisms of tumor cells. ICIs utilize host autoimmune functions for antitumor activity while anti-cancer agents attack the cancer cells directly. However, unfortunately, only a few selected cancer patients responded to this immunotherapy due to different PD-1/PD-L1 expression levels. Infiltrated macrophage and PD-L1 expression in gastric cancer showed high correlation. IL-6 and TNF-α from macrophages induce PD-L1 via the NF-κB and STAT3 signaling pathways. Elevated PD-L1 levels in gastric cancer cells promote the proliferation of gastric cancer cells [81]. IL-6, TNF-α, and PD-L1 may be attractive targets for gastric cancer treatment.

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10092116

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